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Blood, 15 November 2000, Vol. 96, No. 10, pp. 3618-3623
RED CELLS
Molecular analysis of  -aminolevulinate dehydratase
deficiency in a patient with an unusual late-onset
porphyria
Reiko Akagi,
Chiaki Nishitani,
Hideo Harigae,
Yutaka Horie,
Luba Garbaczewski,
A. Hassoun,
R. Mercelis,
L. Verstraeten, and
Shigeru Sassa
From The Rockefeller University, New York, NY; Okayama
Prefectural University, Soja, Japan; Tohoku University School of
Medicine, Sendai, Japan; Universite de Catholique de Louvain, Brussels,
Belgium; and University Hospital of Antwerp, Antwerp, Belgium.
Cloning, expression, and genotype studies of the defective gene for
 -aminolevulinate dehydratase (ALAD) in a patient with an unusual
late onset of ALAD deficiency porphyria (ADP) were carried out. This
patient was unique in that he developed the inherited disease,
together with polycythemia, at the age of 63. ALAD activity in
erythrocytes of the patient was less than 1% of the normal
control level. ALAD complementary DNA (cDNA) isolated from the
patient's Epstein-Barr virus (EBV)-transformed lymphoblastoid cells
had 2 base transitions in the same allele, G177 to C and
G397 to A, resulting in amino acid substitutions K59N and
G133R, respectively. It has been verified that the patient had no other
ALAD mutations in this and in the other allele. By restriction fragment
length polymorphism (RFLP) analysis, all family members of the proband who had one-half ALAD activity compared with the ALAD activity of the
healthy control were shown to have the same set of base transitions.
Expression of ALAD cDNA in CHO cells revealed that K59N cDNA produced a
protein with normal ALAD activity, while G133R and K59N/G133R cDNA
produced proteins with 8% and 16% ALAD activity, respectively,
compared with that expressed by the wild type cDNA. These findings
indicate that while the proband was heterozygous for ALAD deficiency,
the G397 to A transition resulting in the G133R
substitution is responsible for ADP, and the clinical porphyria
developed presumably due to an expansion of the polycythemic clone in
erythrocytes that carried the mutant alad
allele.
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